Effect of 5-benzylacyclouridine, a potent inhibitor of uridine phosphorylase, on the metabolism of circulating uridine by the isolated rat liver

5-Benzylacyclouridine (BAU) is a specific inhibitor of uridine phosphorylase, the first enzyme in the catabolism of uridine. It was found that 20 and 100 μM BAU dramatically reduced the rapid clearance of trace amounts of either [14C]uridine or hyperphysiologic concentrations of non-labeled uridine by the isolated rat liver perfused with an artificial oxygen carrier. In the absence of exogenously added uridine, non-treated livers maintained circulating concentrations of 1-2 μM uridine. In the presence of 20 μM BAU, these concentrations were increased 2- to 3-fold higher than physiologic levels (1.4±0.6 μM) and remained elevated for the duration of the experiment (120-160 min). In the presence of 100μM BAU, uridine concentrations rose continuously at rates of between 80 and ISOnmoles per hr per g of liver, and the clearance of a single radioactive spike of uridine was reduced extensively. The half-life of a uridine spike was extended 2-fold in the presence of 20 μM BAU and 5- to 6-fold in the presence of 100 μM BAU. Exogenously added uridine (15 and 40 μM) was cleared rapidly by nontreated livers, with a half-life of approximately 10 min. However, BAU at a concentration of 20 μM increased the half-life of 15 or 40 μM uridine added to the perfusate by approximately 10-fold. A 100 μM concentration of BAU inhibited the removal of 40 μM circulating uridine, but with 15 μM uridine there was a continuous increase in the circulating concentration similar to that seen in the absence of added uridine. We conclude that extensive inhibition of uridine phosphorylase occurs at 100 μM BAU and partial inhibition at 20 μM BAU. These data indicate independent catabolic and excretory functions of the rat liver with respect to uridine.